Xu Chen, Wang Man-Li, Ling Wei-Hao, Tang Ji-Hong
Department of Neurology, Children's Hospital of Soochow University, Suzhou, China.
Transl Pediatr. 2025 Jun 27;14(6):1353-1361. doi: 10.21037/tp-2025-93. Epub 2025 Jun 18.
Pathogenic variants in , encoding the GluN2A subunit of the N-methyl-D-aspartate receptor (NMDAR), are increasingly recognized as causes of neurodevelopmental disorders, particularly within the epilepsy-aphasia spectrum. However, presentations without clinical seizures-especially those initially manifesting as isolated ataxia-are rarely reported. We describe a previously unreported frameshift variant associated with early-onset ataxia, delayed-onset electrographic abnormalities, and favorable response to immunotherapy.
A 23-month-old boy presented with subacute gait ataxia following a viral illness. Neuroimaging, cerebrospinal fluid analysis, and an extensive autoimmune panel were unremarkable. Initial immunotherapy with high-dose corticosteroids and intravenous immunoglobulin (IVIG) led to transient improvement. Five months later, he developed recurrent ataxia, speech regression, drooling, and global developmental delay, still without overt seizures. Video electroencephalogram (EEG) revealed electrical status epilepticus during slow-wave sleep (ESES) with a spike-wave index exceeding 85%. Trio-based whole genome sequencing identified a novel heterozygous frameshift variant in (c.1717delG, p.Val573Phefs*16), predicted to result in loss of all transmembrane domains. Repeat immunotherapy produced significant clinical improvement, including restored ambulation, cessation of drooling, enhanced speech output, and marked reduction in epileptiform discharges. The patient remained seizure-free during the reported treatment period. Notably, his mother, a carrier of the same variant, reported only a brief history of childhood seizures with minimal residual speech disturbance.
This case expands the phenotypic spectrum of -related disorders to include early isolated ataxia and delayed electrographic epilepsy in the absence of clinical seizures. It highlights the diagnostic value of early genetic testing in atypical neurodevelopmental syndromes and suggests that immunotherapy may confer clinical and electrophysiological benefits, even in presumed NMDAR loss-of-function states. Integration of genomics, neurophysiology, and immune-modulating strategies may inform future precision therapies for -associated encephalopathies.
编码N-甲基-D-天冬氨酸受体（NMDAR）GluN2A亚基的基因中的致病变异越来越被认为是神经发育障碍的病因，尤其是在癫痫-失语谱系中。然而，无临床癫痫发作的表现——尤其是那些最初表现为孤立性共济失调的情况——很少被报道。我们描述了一种先前未报道的移码变异，其与早发性共济失调、迟发性脑电图异常以及对免疫治疗的良好反应相关。
一名23个月大的男孩在病毒感染后出现亚急性步态共济失调。神经影像学检查、脑脊液分析和广泛的自身免疫检查均无异常。最初使用高剂量皮质类固醇和静脉注射免疫球蛋白（IVIG）进行免疫治疗导致短暂改善。五个月后，他出现反复共济失调、言语退化、流口水和全面发育迟缓，仍无明显癫痫发作。视频脑电图（EEG）显示慢波睡眠期间存在癫痫持续状态（ESES），棘波指数超过85%。基于三联体的全基因组测序在该基因中鉴定出一种新的杂合移码变异（c.1717delG，p.Val573Phefs*），预计会导致所有跨膜结构域缺失。重复免疫治疗带来了显著的临床改善，包括恢复行走、停止流口水、言语输出增加以及癫痫样放电明显减少。在报告的治疗期间，患者未再发作癫痫。值得注意的是，他的母亲是同一变异的携带者，仅报告有短暂的儿童癫痫病史，遗留的言语障碍极小。
本病例将该基因相关疾病的表型谱扩展至包括早期孤立性共济失调和无临床癫痫发作的迟发性脑电图癫痫。它突出了早期基因检测在非典型神经发育综合征中的诊断价值，并表明免疫治疗可能带来临床和电生理益处，即使在假定的NMDAR功能丧失状态下也是如此。基因组学、神经生理学和免疫调节策略的整合可能为未来该基因相关脑病的精准治疗提供依据。
